Low-frequency HIV-1 Drug Resistance in Primary HIV-1 Infection

原发性 HIV-1 感染中的低频 HIV-1 耐药性

• 批准号: 7684440
• 负责人: Joanne Donna Stekler
• 金额: $ 42.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684440
• 关键词: Address; Anti-Retroviral Agents; Antiretroviral drug resistance; Biological Assay; Blood; Caring; Clinic; Clinical; Clinical Trials; Consensus Sequence; Consequences of HIV; Data; Detection; Development; Drug resistance; Enrollment; Failure; Frequencies; Future; Genotype; Guidelines; HIV-1; HIV-1 drug resistance; Infection; Intervention; Investigation; Lead; Ligation; Methods; Minority; Modeling; Mutation; Mutation Detection; Natural History; Oligonucleotides; Pattern; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pilot Projects; Plasma; Population; Population Dynamics; Population Surveillance; Prevalence; Probability; Public Health; Reaction Time; Reporting; Research Design; Resistance; Risk; Seminal Plasma; Source; Specimen; Surveillance Program; Test Result; Testing; Time; Treatment Protocols; Treatment outcome; United States; Universities; Variant; Viral; Virus; Washington; antiretroviral therapy; clinical care; clinically relevant; cohort; compliance behavior; design; drug resistant virus; experience; fitness; follow-up; genital secretion; mutant; novel; programs; public health relevance; resistance mutation; response; transmission process

DESCRIPTION (provided by applicant): Public health surveillance programs using consensus sequencing (genotyping) estimate that at least one in ten antiretroviral (ARV)-naive persons infected with HIV-1 in the United States acquires drug resistant HIV-1. Guidelines therefore recommend resistance testing at the time of entry into care. However, consensus sequencing cannot detect low-frequency variants at levels below 10-50% of the viral population. The oligonucleotide ligation assay (OLA) is a more-sensitive assay that can detect mutations occurring in as little as 5% of the viral quasi-species. In a pilot study conducted among subjects with primary HIV-1 infection enrolled at the University of Washington Primary Infection Clinic (PIC), consensus sequencing detected transmitted HIV-1 drug resistance in 6% of 100 subjects, and OLA detected low-frequency mutations in 28 (30%) of 94 subjects who did not have mutations identified by consensus sequencing. We propose studies that will use OLA to address questions pertaining to the transmission and subsequent consequences of HIV-1 drug resistance. In Aim #1, we will study ARV-naive PIC subjects to compare the duration of detection ("persistence") and level of detection of transmitted HIV-1 drug resistance over time in peripheral blood mononuclear cells (PBMCs), blood and seminal plasma. In Aim #2, we will study PIC subjects initiating ARV therapy and use OLA to determine whether additional mutations can be detected in PBMCs during successful treatment due to the selection of transmitted low-frequency drug resistance mutations or the development of new mutations. In Aim #3, we will use OLA to compare HIV-1 drug resistance patterns in PIC subjects and their source partners to determine whether HIV-1 drug resistance impacts "transmission fitness". These novel investigations would broaden our understanding of the natural history and clinical impact of low- frequency HIV-1 drug resistance and inform guidelines for the testing and treatment of HIV-infected persons. If more-sensitive HIV-1 drug resistance assays were to be endorsed for clinical care before there is a full understanding of the relevance of low-frequency mutations, the potential increase in the complexity of initial ARV regimens and subsequent reduction in patient adherence could paradoxically increase the prevalence of drug resistance. Finally, empiric data from partner-pairs will generate information on correlates of HIV-1 transmission that could be incorporated into future models of the population dynamics of drug resistance. These models would estimate the overall proportion of HIV-1 drug resistance that is transmitted from ARV- naive source partners with primary HIV-1 infection versus ARV-experienced source partners with established HIV-1 infection. This data could be used to design public health interventions targeted to these populations to reduce the spread of transmitted HIV-1 drug resistance. PUBLIC HEALTH RELEVANCE: These investigations would broaden our understanding of the natural history and clinical impact of low-frequency HIV-1 drug resistance and inform guidelines for the testing and treatment of HIV-infected persons. Empiric data from partner-pairs could also be used to model population dynamics of drug resistance, quantify the proportion of transmitted HIV-1 drug resistance that is from ARV-naive source partners with primary HIV-1 infection, and develop much- needed public health interventions to reduce the spread of HIV-1 drug resistance.

描述（由申请人提供）：使用共识测序（基因分型）的公共卫生监测计划估计，在美国，未接受过抗逆转录病毒 (ARV) 治疗的 HIV-1 感染者中至少有十分之一获得了耐药性 HIV-1。因此，指南建议在进入护理时进行耐药性测试。然而，共识测序无法检测到低于病毒群体 10-50% 水平的低频变异。寡核苷酸连接测定 (OLA) 是一种更灵敏的测定，可以检测低至 5% 的病毒准种中发生的突变。在华盛顿大学原发感染诊所 (PIC) 登记的原发性 HIV-1 感染受试者中进行的一项试点研究中，共识测序在 100 名受试者中检测到了 6% 的传播性 HIV-1 耐药性，OLA 在 94 名受试者中检测到了 28 名 (30%) 的低频突变，这些受试者没有通过共识测序鉴定出突变。我们提出的研究将使用 OLA 来解决与 HIV-1 耐药性的传播和后续后果有关的问题。在目标 1 中，我们将研究未接受 ARV 的 PIC 受试者，以比较外周血单核细胞 (PBMC)、血液和精浆中传播的 HIV-1 耐药性随时间的检测持续时间（“持久性”）和检测水平。在目标 #2 中，我们将研究开始 ARV 治疗的 PIC 受试者，并使用 OLA 来确定在成功治疗期间是否可以在 PBMC 中检测到由于选择传播的低频耐药突变或新突变的发展而导致的额外突变。在目标 3 中，我们将使用 OLA 比较 PIC 受试者及其来源伙伴的 HIV-1 耐药模式，以确定 HIV-1 耐药性是否影响“传播适应性”。这些新颖的研究将拓宽我们对低频 HIV-1 耐药性的自然史和临床影响的理解，并为 HIV 感染者的检测和治疗提供指导方针。如果在充分了解低频突变的相关性之前就批准更敏感的 HIV-1 耐药性测定用于临床护理，那么初始 ARV 治疗方案复杂性的潜在增加以及随后患者依从性的降低可能会矛盾地增加耐药性的患病率。最后，来自伴侣的经验数据将生成有关 HIV-1 传播相关性的信息，这些信息可以纳入未来的群体耐药动态模型中。这些模型将估计从初次感染 HIV-1 的未接触过 ARV 的来源伙伴与已确诊 HIV-1 感染的经历过 ARV 的来源伙伴传播的 HIV-1 耐药性的总体比例。这些数据可用于设计针对这些人群的公共卫生干预措施，以减少传播的 HIV-1 耐药性的传播。公共卫生相关性：这些调查将拓宽我们对低频 HIV-1 耐药性的自然史和临床影响的理解，并为 HIV 感染者的检测和治疗提供指导方针。来自伴侣对的经验数据还可用于模拟耐药性的人口动态，量化来自初次感染 HIV-1 的 ARV 来源伴侣传播的 HIV-1 耐药性的比例，并制定急需的公共卫生干预措施以减少 HIV-1 耐药性的传播。